Project Summary/Abstract The liver is a major metabolic organ responsible for maintaining whole-body homeostasis in a changing environment. Given the worldwide use of alcohol, the epidemic of obesity and viral infection, liver damage is common in clinical practice. The molecular mechanisms that control the balance between hepatocyte life and death in response to chronic liver injury remain largely elusive. O-linked ?-N-acetylglucosamine (O-GlcNAc) modification has emerged as an important regulatory mechanism underlying normal liver physiology and metabolic disease. This prevalent and dynamic post-translational modification is controlled by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). We recently found that liver-specific OGT knockout mice develop hepatomegaly, ballooning degeneration, and fibrosis in the liver. We therefore hypothesize that OGT acts as a critical molecular switch between hepatocyte survival and death in response to chronic liver injury. To test this hypothesis, we propose to undertake three specific aims. Aim 1 will define the role of OGT in pathogenesis of liver injury; Aim 2 will identify the critical targets of OGT in hepatocyte survival and death; Aim 3 will determine the functional importance of OGT regulation of necroptosis in liver injury. Successful completion of this project will provide critical insights into the role of OGT in regulating the balance between hepatocyte survival and death and the onset of liver injury. Detailed investigation of liver-specific OGT knockout mice will likely establish a useful mouse model that recapitulates features of human liver injury, and facilitate therapeutic target identification for prevention and treatment of chronic liver disease.